Masaru Saita

Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: Combined use of carboxymethyl-ethyl-β-cyclodextrin and penetration enhancers

Abstract— The optimal prescription of transdermal preparations of prostaglandin E1 (PGE1) for treatment of peripheral vascular diseases has been investigated. The chemical stability of PGE1 in fatty alcohol/propylene glycol (FAPG) ointment was markedly improved by carboxymethyl‐ethyl‐β‐cyclodextrin (CME‐β‐CyD). Application of a PGE1 ointment containing the penetration enhancer, 1‐dodecylazacycloheptane‐2‐one (Azone) or 1‐[2‐(decylthio)ethyl]azacyclopentane‐2‐one (HPE‐101), onto the skin of hairless mice showed the increase of blood flow in the skin due to the vasodilating action of PGE1. In particular, the ointment containing a PGE1‐CME‐β‐CyD complex supplemented with HPE‐101 showed the most prominent increase of the blood flow. Compared with other ointments, this ointment was found to show significantly greater transfer of HPE‐101 into in‐vitro preparations of the skin of hairless mice. Transfer of PGE1 into the skin was thought to be facilitated by this increased transfer of HPE‐101. These results suggest that a combination of CME‐β‐CyD and HPE‐101 is useful for designing PGE1 ointments for topical application with good chemical stability and percutaneous permeability.

Combination effects of O-carboxymethyl-O-ethyl-β-cyclodextrin and penetration enhancer HPE-101 on transdermal delivery of prostaglandin E1 in hairless mice

Abstract An inclusion complex of prostaglandin E 1 (PGE 1 ) with β-cyclodextrin (β-Cyd) or O-carboxymethyl-O-ethyl-β-cyclodextrin (CME-β-CyD) was made as topical preparations in a fatty alcohol/propylene glycol ointment base. When the PGE 1 preparations were applied onto the skin of hairless mice, the vasodilating effect of the PGE 1 -CME-β-CyD complex supplemented with a penetration enhancer, 1-[2-(decylthio)ethyl] azacyclopentane-2-one (HPE-101) was approximately 100 times that of the PGE 1 alone and approximately 10 times that of PGE 1 with HPE-101 or the PGE 1 -β-CyD complex with HPE-101. The combination of CME-β-CyD and HPE-101 enhanced the percutaneous penetration of PGE 1 in a synergistic manner; CME-β-CyD assisted the release of HPE-101 from the ointment base and its entry into the skin which may facilitate the percutaneous penetration of PGE 1 . Furthermore, this combination suppressed the bioconversion of PGE 1 to give less pharmacologically active metabolites during the passage through the skin, a situation delivering intact PGE 1 more effectively to the site of action. The present data suggest that the combination of CME-β-CyD and HPE-101 is particularly useful for improving topical bioavailability of PGE 1 .

DEVELOPMENT OF TOLERANCE TO 1-(m-TRIFLUOROMETHYLPHENYL)-3-(2-HYDROXYETHYL)-QUINAZOLINE-2, 4(1H, 3H)-DIONE [H-88]

Tolerance was provoked to all the pharmacological activities of H-88 examined, such as anti-inflammatory (Carrageenin-induced rat paw edema), analgetic (Tail pressure method in mice), hypothermic (Rectal temperature in mice), hypomotor activity (Wheal cage method in mice), prolongation of the sleeping time induced by pentobarbital Na (rats and mice), depression of gastric emptying and intestinal transport (rats) and stimulation to hypothalmo-hypophyse-adrenal axis (rats). The effect of H-88 on the pentobarbital Na-induced sleeping time in rats was not dissipated by adrenalectomy, and did not depend on the depression of intestinal absorption. The development of tolerance to H-88 was antagonized by ethionine pretreatment. It is suggested that tolerance to H-88 is mainly due to the hepatic enzyme induction.